This article discusses a recent FDA workshop held for troponin assays, tests designed most commonly to detect the release of cardiac troponin following Acute Myocardial Infarction (AMI). The authors review the history, uses and issues associated with using troponin - a three protein complex, released rapidly into the blood after myocardial injury - and innovative medical devices to detect troponin levels, as an assay to aid in the diagnosis of an AMI event. Regulatory professionals working with companies seeking clearance of troponin assay devices need to be aware that the pathway to clearance does not conform to the traditional method comparison approach.
On 28 November 2017, the US Food and Drug Administration (FDA) held a public workshop entitled "Cardiac Troponin Assays."1 The purpose of the workshop was to discuss the development of innovative troponin assays designed to aid in the diagnosis of Myocardial Infarction (MI) and additional clinical uses. The workshop was aimed at enhancing engagement with stakeholders to better facilitate troponin assay device development and to discuss scientific and regulatory challenges associated with the analytical and clinical validation methods for those devices.
What is troponin?
Cardiac troponin is a protein composed of three subunits found in skeletal and cardiac muscles. Cardiac troponins are released rapidly into the blood after myocardial injury (cell death) and are measureable using technologies readily available from diagnostic manufactures using both large clinical analyzers and point-of-care devices.2 The utility in measuring cardiac troponin is largely focused on use in the emergency room setting in the diagnosis and management of patients with suspected Acute Coronary Syndrome (ACS). More recent technologies, referred to as "high-sensitivity" troponin assays, can measure naturally occurring troponin levels in most, if not all, people. These technologies are changing the regulatory landscape even as FDA struggles with their clearance.
How does the assay work and what kind of data does it provide?
The development and use of troponin assays has a long history with European agencies clearing devices for use years ago. FDA has been slower to approve troponin assay devices for a number of reasons. A 2017 FDA letter noted:
In 2007, the National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines and the Joint ESC/ACCF/AHA/WHF Task Force Guidelines recommended the use of cardiac troponin as a biomarker for the diagnosis of Myocardial Infarction (MI) when used in conjunction with clinical evidence of myocardial ischemia. These recommendations solidified troponin's importance in MI diagnosis and triage; at the same time, they formalized an adjustment in the clinical cutoffs and changed the way troponin results were interpreted and used.3,4
However, there has been some international cooperation and consensus regarding the utility and efficacy of troponin assays. For example, the 2012 European Society of Cardiology/American College of Cardiology/American Health Association/World Health Federation (ESC/ACC/AHA/WHF) expert consensus document for the definition of acute myocardial infarction included information on the measurements of cardiac troponin.5 The expert consensus document said the detection of a rise and/or fall of cardiac-troponin concentrations, with at least one measurement elevated above the 99th percentile (upper reference limit) of a presumably healthy reference population, was central to the ESC/ACC/AHA/WHF third universal definition of AMI.
An elevated cardiac troponin concentration has become an indication of myocardial necrosis, but not indicative of the underlying mechanism causing the injury. Apart from AMI, cardiac troponins can be elevated in non-ischemic conditions and conditions associated with secondary ischemic injury, such as myocarditis, congestive heart failure, stable Coronary Artery Disease (CAD), unstable angina, arrhythmias, cardiac trauma, pulmonary embolism, renal failure, septicemia, and chemotherapy. Therefore, serial cardiac-troponin measurements are recommended for patients presenting with chest pain. In accordance with current FDA requirements for the diagnosis of AMI, cTnI and cTnT findings (two kinds of cardiac troponins) must be interpreted in conjunction with clinical presentation, electrocardiography, and imaging.
What clinical and analytical information is needed to understand the clinical performance of a troponin device?
Key performance characteristics driving the value of troponin assays for the clinician, laboratory, and patient are lower limits of detection, better precision at the limit of quantitation, and at the Upper Limit of Normal (ULN). These factors, plus rapid turn-around time from sample collection to reporting of results, drive the clinical utility of these products.
Based on the criticality of the cardiac troponin results to a patient's diagnosis of AMI, in 2010 FDA issued letters to manufacturers of cardiac troponin assays indicating that 510(k) submissions based solely on method comparison studies for establishing substantial equivalence were no longer appropriate.6 Rather, submissions based on adjudicated MI became the standard. This required manufacturers to engage in costly prospective clinical trials and has over time slowed the progress for FDA clearance on these assays.
In Europe, such assays are designated as "self-certified" by the European Union (EU) under the In Vitro Diagnostic Directive (IVDD) regulation.7 Therefore, availability in the EU market was achieved more rapidly.
Notice to Regulatory Professionals
Regulatory professionals working with companies seeking the clearance of troponin assays need to know the pathway to clearance does not conform to the traditional method comparison approach. In conjunction with its letters issued in 2010, FDA published a guidance document outlining what would be required for the clearance of cardiac troponin assays. This guidance was withdrawn shortly after being issued. Despite this action, FDA review of recently cleared troponin assays, as well as pre-submissions to FDA for feedback on the data required for achieving clearance of newer cardiac troponin assays, has created a successful path toward aligning FDA and manufacturer clearance expectations.
Open Communication Between FDA and Stakeholders
Open communication between FDA and stakeholders was one goal of the November 2017 workshop. Stakeholders attending the workshop included clinicians, laboratorians, manufacturers, and FDA personnel. All of these parties have a stake in these important products becoming available in the market, but accompanied by robust clinical information to support the validity of the tests. However, there are varying opinions among all parties on how to best achieve this goal. Consequently, a number of issues were broadly debated during the workshop.
Workshop Discussions, Issues and Shared Goals
To address these specific questions, FDA's workshop included discussions relating to reference range studies and clinical trial design. Reference range studies are used to establish ULN or to set the MI cutoff for troponin assays. The purpose for establishing a ULN is to determine that patients in the intended use population with results below the ULN are not having an AMI, and any patient with a result above the ULN, are considered to be having or have had an MI. The problems with this blanket approach were discussed by the panel addressing the questions: What is "normal" in a patient population covering an age range that is likely to include subjects with some type of underlying heart condition? Is a patient with a troponin result immediately above the ULN diagnosed as MI? As high-sensitivity troponin assays are demonstrating, all humans have detectable troponin to measure of cell death. Just as other cells in the body turn over with time, so does heart muscle tissue. Therefore, some patients with no risk of MI have troponin levels above the ULN because of other conditions. FDA looked to the panel to provide input for better guidance on how the ULN should be established, and going forward, what should be the utility of the ULN.
Clinical trial designs require that patients presenting to the Emergency Department (ED) with specific conditions related to the intended use of the device be enrolled as "all comers" in the clinical trial. Challenges raised by the panel and manufacturers included the need to collect a baseline sample as soon as possible and how - under such conditions - informed consent could be obtained in a timely manner. It was suggested it would be unethical to delay other emergency diagnostic procedures - such as cardiac catheterization - to obtain informed consent from the patient. In the best interests of the patient, as well as in the interests of the clinical trial, obtaining informed consent in a timely manner remains a challenging issue.
Standardizing and Harmonizing
Ongoing work is being sponsored by clinical leaders in the troponin space who are seeking ways to standardize troponin assays. One potential method is establishing a clinical sample bank—similar to a College of American Pathologists (CAP) survey—but specifically focused on a panel of patient samples collected from emergency room settings that are well characterized and could be used by all companies. A recent paper published in Clinical Chemistry describes the need for harmonizing and standardizing troponin assays.8 The authors proposed a second option to replace currently used standard reference material with a commutable, serum-based material being developed and validated by the National Institute of Standards and Technology.
Stability Issues and Biotin Interference With Troponin Assay Devices
The stability of samples for use with troponin assays is part of the analytical performance studies required for any regulatory submission. Properly designed studies to repeatedly measure detectable troponin from patient samples mitigate the risk of potential instability.
With the broad availability of over-the-counter biotin supplements - a largely unregulated space - biotin interference has become a recent issue. On the day the troponin workshop was held, FDA issued a safety communication from their website titled, "FDA Warns That Biotin may Interfere With lab Tests," describing the risks associated with testing for troponin from patients taking biotin supplements.9 Manufacturers also are being directed to test for biotin as part of their analytical testing for submission to FDA.
Cardiac troponin device innovation has been a focus of manufacturers for many years. While some companies are on their fourth or fifth generation tests, others are pursuing their first troponin product. In both instances, the goal of the innovation is lowering the detectable threshold for troponin so that clearer distinctions can be detected between normal troponin and changes in troponin levels. Given this goal, the regulatory hurdles to achieving clearance of high-sensitivity troponin assays have increased. As a result, only one company in the past five years has achieved successful clearance to market the product. In working with FDA on these workshops, it is the industry's hope that FDA will be able to move more products through the pipeline so that these important technologies can reach clinicians, laboratorys, and patients. It is important for companies supporting manufacturers interacting with FDA to develop strong relationships with FDA reviewers and reach a deep understanding of how to achieve the goals of both manufacturers and FDA.
- Public Workshop - Cardiac Troponin Assays, November 28, 2017. FDA website. https://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm569048.htm. Accessed 6 February 2018.
- Overview: Cardiac Troponin Assays. Public Workshop. November 28, 2017. FDA website. https://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM586774.pdf. Accessed 6 February 2018.
- Universal Definition of Myocardial Infarction - Circulation 2007: 116, 2634-2653.
- European Society of Cardiology (ESC) Congress 365. ESC website. http://congress365.escardio.org/Session-Reports. Accessed 6 February 2018.
- Thygesen, K, Alpert, J.S., Jaffe, A.S., Simoons, M.L., Chaitman, B.R. and White, H.D. and the writing group. ESC/ACCF/AHA/WHF Expert Consensus Document. Third Universal Definition of Myocardial Infarction. October 2012. https://doi.org/10.1161/CIR.0b013e31826e1058. Accessed 7 February 2018.
- Letter to Manufacturers of Troponin Assays Listed with the FDA. FDA website. https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm230118.htm. Accessed 6 February 2018.
- In Vitro Diagnostic Medical Devices. http://ec.europa.eu/growth/single-market/european-standards/harmonised-standards/iv-diagnostic-medical-devices/. Accessed 6 February 2018.
- Plebani, M. "Harmonization of Clinical Laboratory Information - Current and Future Strategies." JIFCC website. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4975213/. Accessed 6 February 2018.
- Biotin (Vitamin B7): Safety Communication - May Interfere with Lab Tests. FDA website. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm586641.htm. Accessed 6 February 2018.
About the Authors
Karen Richards is Precision Medicine Group's vice president, in vitro diagnostics and quality leader and innovator in the GMP/ISO/FDA/EU-regulated In Vitro Diagnostic (IVD) industry. She spearheads regulatory approvals worldwide for both novel and traditional IVD assays and products, as well as laboratory developed tests in the US. She builds ground-up quality systems, meeting the requirements of US FDA, International Standards Organization (ISO) 13485, Clinical Laboratory Improvement Act (CLIA), and College of American Pathologists (CAP). She can be contact at Karen.Richards@precisionformedicine.com.
Judi Smith is Precision Medicine Groups' vice president, in vitro diagnostics and quality. She is an expert in IVD services spanning regulatory strategy, analytical and clinical study designs, protocol development, all FDA pre-market and post-market submissions, software lifecycle documentation, quality-system establishment, and laboratory developed test set-up by CLIA and FDA regulations. She can be contact at Judi.Smith@precisionformedicine.com.
Cite as: Richards, K. and Smith, J. "FDA's Workshop on Troponin Assays Approval Fosters Agreement, Debate." Regulatory Focus. February 2018. Regulatory Affairs Professionals Society.